Typhoid fever remains a serious cause of morbidity and mortality in under-developed nations. The immunopathogenic role of the capsular polysccharide of Salmonella typhi (Vi), the causative agent of typhoid fever, remains controversial. There is much evidence the serum Vi antibodies could confer protection against typhoid fever. Typhoid fever is a disease of humans only; there is no satisfactory animal model. Clinical studies are required therefore, to evaluate the effectiveness of Vi vaccination to induce antibodies against typhoid fever. Collaborative studies with Dr. H. Koornhof, South African institute for Medical Research, Dr. I. L. Acharya, Infectious Disease Hospital Kathmandu, Nepal, and Dr. Ramesh Kumar, All India Institute of Medical Sceinces, New Delhi, India, have been established to study the prevalence of Vi antibodies in the general population, the age-specific attack and the effectiveness of vaccines designed to induce Vi antibodies. A Vi antibody assay has been established as an accurate, sensitive method to identify carriers. Four surveys of Vi antibodies in populations with different attack rates of typhoid have been completed. The first measured Vi antibodies in U.S. armed forces recruits injected with the typhoid bacterial vaccine. Pre-immune Vi antibodies were less than 0.2 Mug/ml in 49/50. Three surveys in individuals of various agegs in Chile, Eastern Transvaal, and Kathmandu, showed that adults had considerably higher Vi antibodies than those in the U.S. Vi antibodies elicited by the whole cell vaccine and by injection of Vi were comparable. Post-immunization levels of Vi antibodies were, however, lower than those induced by typhoid fever and those elicited by other capsular polysaccharide vaccines. Vi polysaccharide with lower LPS content has been prepared by the Institut Merieux and will be studied in Nepal and in Eastern Transvaal. A Vi-Cholera toxin conjugate has beeen prepared and standardized; it is about 15 times more immunogenic in mice than the Vi alone. Clinical studies with this new vaccine are being planned.